Multiple Myeloma: Novel Agents. Robert A. Kyle, M.D. Germany June 28, Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Transcription

1 Multiple Myeloma: Novel Agents Robert A. Kyle, M.D. Germany June 28, 2008 Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

2 Multiple Myeloma Untreated Initial Therapy Transplant eligible

3 Multiple Myeloma Untreated N = 470 Resp TTP DVT CR/PR mos % % (med) Thal mg/day + Dex 40mg(day 1-4, , ) Placebo + vs. Dex 40mg (day 1-4, , ) Rajkumar et al., JCO 26:2171, 2008

4 Survival Rate N Survival Probability One-Year Two-Year % % Lenalidomide 25 mg d Dexamethasone 40 mg d 1-4, , vs. Lenalidomide 25 mg d Dexamethasone 40 mg d 1, 8, 15, Rajkumar, et al., ASCO 2008

5 Overall Survival (months) Rd RD Rajkumar, et al., JCO 25:18S, 2007 (ASCO)

6 Multiple Myeloma Untreated N = 48 Response Bortezomib 1.3 mg/m2 % 2/wk x 2 q3 wks CR/NCR 19 + Dexamethasone 40 mg Day of and day after Bortezomib PR 71 if no response Total 90 Jagannath, et al., Blood 108: 238a, 2006

7 Multiple Myeloma Untreated Initial therapy Transplant ineligible CP

8 Multiple Myeloma Untreated age years IFM N= 447 PFS med mos OS med mos MPT (400 mg) x MP x VAD/Mel 100x Facon, et al., Lancet, :1209

9 Multiple Myeloma Untreated age > 75 years IFM 01/01 N= 229 PFS med mos OS med mos MPT (100 mg) d 1-4, 1 q. 6 weeks x M 0.2 mg/kg + P 2 mg/kg d q. 6 weeks x 12 Hulin, et al., Blood 2007, 110:31a

10 San Miguel, et al, ASH 2007 Multiple Myeloma Non-Transplant Candidates Cycles 1-4 Bortezomib 1.3 mg/m2 IV d 1,4,8,11,22,25,29,32 + Melphalan 9 mg/m2 and prednisone 60 mg/m2 d 1-4 Cycles 5-9 Bortezomib 1.3 mg/m2 IV d 1,8,22,29 + Melphalan 9 mg/m2 and prednisone 60 mg/m2 d 1-4 vs. Melphalan 9 mg/m2 and prednisone 60 mg/m2 d 1-4 Nine 6-week cycles of both arms

11 Multiple Myeloma Response to Treatment MPV MP N=336 N=331 p-value M-protein* M-protein* M CR (IF-) 35% 5% < VGPR (>( 90% ÄM-protein) 10% 5% PR 46% 45% *measured in serum or urine by centralized laboratory San Miguel, et al., ASH 2007

12 Multiple Myeloma Grade 3/4 adverse events (%) VMP (n=340) MP (n=337) Gr 3 Gr 4 Gr 3 Gr 4 Neutropenia Thrombocytopenia Anemia GI <1 Peripheral Sensory Neuropathy 13 <1 0 0 Fatigue Asthenia 6 <1 3 0 Pneumonia Herpes Zoster Transfusion (26% vs 35%) and EPO support (34% vs 42%) were somewhat lower on the VMP arm PN resolved or improved in 75% of cases in a median of 64 days DVT was low and the same on both arms (1%) San Miguel, et al., ASH 2007

13 Multiple Myeloma Treatment Relapsed, Refractory

14 Refractory Multiple Myeloma Therapy Vcr Adria Dex (VAD) High-dose corticosteroids Dexamethasone 40 mg d 1 4, 9 12, q mo Thalidomide Bortezomib (Velcade) Lenalidomide (Revlimid)

15 Single-Agent Thalidomide in Recurrent/Refractory Multiple Myeloma Dose Pt RR Study (mg/d) (no.) (%) Singhal, et al * Barlogie, et al ** Grosbois (incl minor response) * >25% Ä in paraprotein ** 2-yr event-free survival and overall survival rates of 20% and 48%, respectively CP

16 Refractory Multiple Myeloma Treatment Bortezomib (VELCADE TM ) (PS-341) n = 193 Response (CR/PR) 35% Duration response 12 mo Richardson et al: NEJM 2003, 348:26.

17 Multiple Myeloma Relapsed Bortezomib, 1.3 mg/m 2 d 1, 4, 8, 11 q 3wks vs. N = 669 Dexamethasone, 40 mg d 1-4; ; TTP mos Survival med mos Richardson, et al., Blood, 2007, 110:3557

18 Multiple Myeloma Relapsed/Refractory Bortezomib, 1.3 mg/m 2 IV d 1, 4, 8, 11 vs. N = 646 Bortezomib, 1.3 mg/m 2 IV d 1, 4, 8, 11 + Doxil 30 mg/m 2 IV d 4 Orlowski et al., JCO, 2007, 25:3892 TTP Survival mos at 15 mos med %

19 Lenalidomide 25 mg d Dexamethasone 40 mg d 1-4, , vs. Placebo d Dexamethasone 40 mg d 1-4, , Multiple Myeloma Relapsed/Refractory 009,010 N = 704 Response CR/PR TTP % Mos (Med) Weber, et al., NEJM, 2007, 357:2133; Dimopoulos, et al., NEJM, 2007, 2 357:2123

20 1.0 Multiple Myeloma n=2,981 Proportion surviving Survival, med 29.9 mo Kumar et al: Blood 111:2516, 2008 Survival, med 44.8 mo Diagnosis during/ before 1996 Diagnosis after 1996 Time from diagnosis (months) P<0.001 CP

21 Proportion surviving Relapse After Autologous Transplant for Multiple Myeloma n=161 Survival, med 30.9 mo Kumar et al: Blood 111:2516, 2008 Exposed to new drugs n=226 Survival, med 14.8 mo No exposure to new drugs n=387 P<0.001 Time from post-asct relapse (months) CP

22 Multiple Myeloma Novel Agents Histone deacetylase inhibitor SAHA Heat Shock protein- 90 inhibitor KOS-953 Tanespimycin VEGF Inhibitors Farnesyl transferase inhibitor Arsenic Trioxide Proteosome inhibitor (oral) FGFR3 inhibitor P 38 MAPK inhibitor PTK787/2K SCH Trisenox NPI-005 Chir-258 Scio-469

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